Methods for concomitant treatment of theophylline and febuxostat

ABSTRACT

The present disclosure relates to a method of treating hyperuricemia in a patient that also suffers from a second disease state requiring treatment with theophylline, wherein the patient receives concomitant treatment with a xanthine oxidoreductase inhibitor and theophylline without resulting in theophylline toxicity to the patient and without substantial adjustments to the manufacturer&#39;s recommended dosage of theophylline.

RELATED APPLICATION INFORMATION

This is a continuation of U.S. patent application Ser. No. 13/227,828,filed on Sep. 8, 2011, which claims priority to U.S. Provisional PatentApplication No. 61/381,482, filed on Sep. 10, 2010, the contents of allof which are herein incorporated by reference in their entirety.

FIELD

The present disclosure relates to novel methods for treatinghyperuricemia in patients also requiring treatment with theophylline.Specifically, the invention is directed to a method of administeringtheophylline in conjunction with one or more xanthine oxidoreductaseinhibitors, whereby the xanthine oxidoreductase inhibitors do not causealterations in the plasma concentrations of theophylline.

BACKGROUND

A substantial number of patients are affected with diseases of therespiratory system, including asthma, acute bronchitis, chronicbronchitis, emphysema, neonatal apnea, and neonatal bradycardia. One ofthe primary treatments for respiratory diseases is the use oftheophylline

Theophylline is a useful medicine frequently used as an agent fortreating symptoms of bronchial asthma. It is known in the art thateffective blood concentrations range from about 10 to 20 μg/ml. However,if the concentration of theophylline in the blood exceeds 20 μg/ml,serious side effects sometimes appear with regard to the cardiovascularsystem and the central nervous system. Further, there is a largedifference in blood levels among individuals. Various conditions (e.g.,cardiac insufficiency, liver and kidney disease, etc.), age differences,smoking, etc. also have large effects. Additionally, theophylline has ashort biological half-life of about 6 hours for adults. In order tomaintain the effective blood level, four doses per day have beenconsidered necessary. However, such frequent dosing is troublesome topatients, reduces patient compliance, and causes the state of thedisease to become worse. In particular, attacks of bronchial asthmaoften occur at daybreak. It is not possible to sufficiently prevent suchattacks with ingestion of theophylline just before going to bed, andtherefore, repeat ingestion close to daybreak is necessary. Thus, in thepast, continuous effort has been made to develop a sustained releasetype theophylline formulation. Several formulations are alreadyavailable on the market.

Another disease that affects a substantial number of patients is gout.Gout affects 3 to 5 million individuals in the United States of America(USA) and is increasing in incidence and prevalence. Gout is a serioushealth condition characterized by flares of acute arthritis, chronicgouty arthropathy, tophi, and uric acid urolithiasis, and is associatedwith a broad range of comorbidities, including cardiovascular disease,chronic kidney disease, and metabolic syndrome. At the joint level, agout flare is best characterized as an acute monoarthritis arthropathyprocess with proliferative bone reaction that can affect any joint andthat can later develop into chronic polyarthritis. Gout attacks tend tooccur mostly in the lower extremities and over time additional jointscan be involved.

The underlying metabolic aberration in gout is hyperuricemia, which is acondition defined as an elevation in serum urate (sUA) level ≧6.8 m/dL.Hyperuricemia develops into gout when urate crystals are formed fromsupersaturated body fluids and deposited in joints, tophi, andparenchymal organs due to a disorder in the urate metabolism. Uric acidis the end product of purine metabolism and is generated in the cascadeof hypoxantine→xanthine→uric acid.

Urate-lowering therapy (ULT) is used to treat hyperuricemia in subjectswith gout. The goal of ULT is to reduce sUA to 6.0 mg/dL or less, belowthe concentration at which monosodium urate saturates extracellularfluid. Using ULT to reduce and maintain sUA levels <6.0 mg/dL ultimatelyimproves the clinical symptoms of gout by reducing the frequency of goutflares, decreasing size and number of tophi, and improving quality oflife. One alternative that may be used for the treatment of gout is theadministration of xanthine oxidase inhibitors, such as allopurinol.Generally, allopurinol is considered one of the primary treatments ofgout and has developed wide usage as a treatment for gout.

However, clinicians have few treatment options for hyperuricemicpatients also suffering from respiratory diseases, such as chronicobstructive pulmonary disease, asthma, acute bronchitis, chronicbronchitis, emphysema, neonatal apnea, and neonatal bradycardia. One ofthe primary treatments for these respiratory diseases is theadministration of theophylline, a bronchodilator. Although theophyllineprovides a treatment for the respiratory diseases described herein, thetherapeutic range of theophylline blood concentrations is thought to bevery narrow, ranging from about 10 to about 20 μg/ml. As such, if thetheophylline dosing does not provide a minimum blood concentration of 10μg/ml, the patient is not provided significant relief from therespiratory condition, and at blood concentrations greater than 20μg/ml, the patient may be susceptible to adverse effects such asabdominal pain, headache, muscle cramps, tremors, tachycardia, andseizures. Therefore, clinicians must exercise caution in determiningtreatment options for patients requiring theophylline treatment, andmust closely monitor the potential for drug interactions that mayincrease or decrease theophylline blood concentrations.

It is further known within the art that the administration ofallopurinol interacts with the metabolism of theophylline, causing thetheophylline to be metabolized slowly, and leading to increased bloodconcentrations. As discussed in the art, the area under the curve (AUC)for theophylline in patients co-administered allopurinol andtheophylline has been reported to increase by up to 27%, the half-lifeincreased by approximately 25%, and the clearance of theophylline may bedecreased by 21% (Manfredi B A, et al., Clin. Pharmacol. Ther., 1981;29(2), pp. 224-229). Accordingly, clinicians are required to alter thetheophylline dosing and/or the allopurinol dosing in hopes ofestablishing a therapeutic dose for both disease states, while avoidingunwanted adverse effects that may result from increased theophyllineconcentrations.

Thus, in view of these considerations, there exists within the art aneed to develop a treatment option for hyperuricemic patients that alsosuffer from respiratory disorders, whereby the clinician can administertypical dosing of theophylline without adjusting for adverse druginteractions.

SUMMARY

The present disclosure is directed to methods for treating hyperuricemiain patients requiring treatment with theophylline. The methods of thecurrent invention avoid the drug interactions typically associated withtheophylline administration and concomitant treatment with xanthineoxidase inhibitors.

In one embodiment, the present disclosure provides a method of treatinghyperuricemia in a patient in need of treatment thereof, the methodcomprising the steps of: administering to the patient suffering fromhyperuricemia and at least one secondary disease state, atherapeutically effective amount of at least one xanthine oxidoreductaseinhibitor, wherein said subject is also receiving a concomitantadministration of theophylline to treat the at least one secondarydisease state; and further wherein (i) the administration of the atleast one xanthine oxidoreductase inhibitor to said patient does notresult in theophylline toxicity to said patient; and (ii) administrationof the theophylline is in an amount ranging from about 90% to about 110%of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.

The secondary disease state may include asthma, acute bronchitis,chronic bronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof. As described in the method of this embodiment, thexanthine oxidoreductase inhibitor may include2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole andpharmaceutically acceptable salts thereof.

Moreover, the method of the current embodiment may include atheophylline dose ranging from about 95% to about 105%, and from about99% to about 101% of a manufacturer's recommended theophylline dosageamount in the absence of administration of at least one xanthineoxidoreductase inhibitor. The method of the current invention may alsoinclude patients suffering from a third disease state, including gout,hypertension, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty joint disease, tophaceous gout, uric acid urolithiasis,uric acid nephropathy, progressive renal disease, and combinationsthereof. Further, the methods of the current embodiment include thetreatment of hyperuricemia in patients that were previously receivingtheophylline treatment prior to treatment with a xanthine oxidoreductaseinhibitor.

In another embodiment, the current invention provides a method oftreating hyperuricemia in a patient in need of treatment thereof, themethod comprising the steps of: administering to the patient sufferingfrom hyperuricemia and at least one second disease state, atherapeutically effective amount of at least one xanthine oxidoreductaseinhibitor, wherein said subject will also be receiving a concomitantadministration of theophylline to treat at least one second diseasestate, and further wherein (i) the administration of the at least onexanthine oxidoreductase inhibitor to said patient will not result intheophylline toxicity to said patient; and (ii) administration of thetheophylline will be in an amount ranging from about 90% to about 110%of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.

The secondary disease state may include asthma, acute bronchitis,chronic bronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof. As described in the method of this embodiment, thexanthine oxidoreductase inhibitor may include2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole andpharmaceutically acceptable salts thereof.

Moreover, the method of the current embodiment may include atheophylline dose ranging from about 95% to about 105%, and from about99% to about 101% of a manufacturer's recommended theophylline dosageamount in the absence of administration of at least one xanthineoxidoreductase inhibitor. The method of the current invention may alsoinclude patients suffering from a third disease state, including gout,hypertension, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty joint disease, tophaceous gout, uric acid urolithiasis,uric acid nephropathy, progressive renal disease, and combinationsthereof. Further, the methods of the current embodiment include thetreatment of hyperuricemia in patients that have not previously receivedtheophylline treatment prior to treatment with a xanthine oxidoreductaseinhibitor, and will begin treatment with both medications concurrently.

In yet another embodiment, the present disclosure provides a method oftreating hyperuricemia in a patient suffering from gout and in need oftreatment thereof, the method comprising the steps of: administering tothe patient suffering from gout and hyperuricemia and at least one thirddisease state, a therapeutically effective amount of at least onexanthine oxidoreductase inhibitor, wherein said subject is alsoreceiving a concomitant administration of theophylline to treat the atleast one third disease state; and further wherein (i) theadministration of the at least one xanthine oxidoreductase inhibitor tosaid patient does not result in theophylline toxicity to said patient;and (ii) administration of the theophylline is in an amount ranging fromabout 90% to about 110% of a manufacturer's recommended theophyllinedosage amount in the absence of administration of at least one xanthineoxidoreductase inhibitor.

The third disease state may include asthma, acute bronchitis, chronicbronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof. As described in the method of this embodiment, thexanthine oxidoreductase inhibitor may include2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole andpharmaceutically acceptable salts thereof.

Moreover, the method of the current embodiment may include atheophylline dose ranging from about 95% to about 105%, and from about99% to about 101% of a manufacturer's recommended theophylline dosageamount in the absence of administration of at least one xanthineoxidoreductase inhibitor. The method of the current invention may alsoinclude patients suffering from a fourth disease state, includinghypertension, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty joint disease, tophaceous gout, uric acid urolithiasis,uric acid nephropathy, progressive renal disease, and combinationsthereof. Further, the methods of the current embodiment include thetreatment of hyperuricemia in patients suffering from gout and that werepreviously receiving theophylline treatment prior to treatment with axanthine oxidoreductase inhibitor.

In another embodiment, the current invention provides a method oftreating hyperuricemia in a patient suffering from gout and in need oftreatment thereof, the method comprising the steps of: administering tothe patient suffering from gout and hyperuricemia and at least one thirddisease state, a therapeutically effective amount of at least onexanthine oxidoreductase inhibitor, wherein said subject will also bereceiving a concomitant administration of theophylline to treat at leastone third disease state, and further wherein (i) the administration ofthe at least one xanthine oxidoreductase inhibitor to said patient willnot result in theophylline toxicity to said patient; and (ii)administration of the theophylline will be in an amount ranging fromabout 90% to about 110% of a manufacturer's recommended theophyllinedosage amount in the absence of administration of at least one xanthineoxidoreductase inhibitor.

The third disease state may include asthma, acute bronchitis, chronicbronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof. As described in the method of this embodiment, thexanthine oxidoreductase inhibitor may include2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole andpharmaceutically acceptable salts thereof.

Moreover, the method of the current embodiment may include atheophylline dose ranging from about 95% to about 105%, and from about99% to about 101% of a manufacturer's recommended theophylline dosageamount in the absence of administration of at least one xanthineoxidoreductase inhibitor. The method of the current invention may alsoinclude patients suffering from a fourth disease state, includinghypertension, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty joint disease, tophaceous gout, uric acid urolithiasis,uric acid nephropathy, progressive renal disease, and combinationsthereof. Further, the methods of the current embodiment include thetreatment of hyperuricemia in patients that have not previously receivedtheophylline treatment prior to treatment with a xanthine oxidoreductaseinhibitor, and will begin treatment with both medications concurrently.

In still yet another embodiment, the present disclosure provides amethod of treating a patient in need of treatment thereof, the methodcomprising the steps of: administering to the patient suffering from atleast one first disease state and at least one secondary disease state,a therapeutically effective amount of at least one xanthineoxidoreductase inhibitor, wherein said subject is also receiving aconcomitant administration of theophylline to treat the at least onesecondary disease state; and further wherein (i) the administration ofthe at least one xanthine oxidoreductase inhibitor to said patient doesnot result in theophylline toxicity to said patient; and (ii)administration of the theophylline is in an amount ranging from about90% to about 110% of a manufacturer's recommended theophylline dosageamount in the absence of administration of at least one xanthineoxidoreductase inhibitor.

The first disease state may include gout, prostatitis, inflammatorybowel disease, QT interval prolongation, myocardial infarction, cardiachypertrophy, hypertension, nephrolithiasis, renal impairment, chronickidney disease, metabolic syndrome, diabetes, diabetic nephropathy,congestive heart failure and combinations thereof.

The secondary disease state may include asthma, acute bronchitis,chronic bronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof. As described in the method of this embodiment, thexanthine oxidoreductase inhibitor may include2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole andpharmaceutically acceptable salts thereof.

Moreover, the method of the current embodiment may include atheophylline dose ranging from about 95% to about 105%, and from about99% to about 101% of a manufacturer's recommended theophylline dosageamount in the absence of administration of at least one xanthineoxidoreductase inhibitor. The method of the current invention may alsoinclude patients suffering from a third disease state, including gout,hypertension, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty joint disease, tophaceous gout, uric acid urolithiasis,uric acid nephropathy, progressive renal disease, and combinationsthereof. Further, the methods of the current embodiment include thetreatment of the first disease state in patients that were previouslyreceiving theophylline treatment prior to treatment with a xanthineoxidoreductase inhibitor.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows the mean theophylline plasma concentration-time profilesfollowing an oral dose of 400 mg theophylline coadministered with 80 mgof 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid (also known as “febuxostat”) or matching placebo as described inExample 1.

DETAILED DESCRIPTION OF THE DISCLOSURE I. Definitions

Section headings as used in this section and the entire disclosureherein are not intended to be limiting.

As used herein, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. For therecitation of numeric ranges herein, each intervening number therebetween with the same degree of precision is explicitly contemplated.For example, for the range 6-9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated.

As used herein, the term “about” is used synonymously with the term“approximately.” Illustratively, the use of the term “about” indicatesthat values slightly outside the cited values, namely, plus or minus10%. Such dosages are thus encompassed by the scope of the claimsreciting the terms “about” and “approximately.”

As used herein, the term “AUC” refers to the area under the plasmaconcentration time curve of the active agent and which is calculatedusing the trapezoidal rule. The term “AUC_(t)” means the area under theplasma concentration time curve from time 0 to 120 hours afteradministration in units of ng·h/mL as determined using the trapezoidalrule. The term “AUC∞” means the area under the plasma concentration timecurve from time 0 to infinite time. AUC∞ is calculated asAUC_(t)+LMT/(−β), where “LMT” is the last measurable plasmaconcentration and β is the terminal phase elimination rate constant.Unless otherwise noted herein, the reported value for the AUC is thecentral value of the AUC. The “central value” of the AUC is the meanAUC±standard deviation.

The terms “administer”, “administering”, “administered” or“administration” refer to any manner of providing a drug (such as, axanthine oxidoreductase inhibitor or a pharmaceutically acceptable saltthereof) to a subject or patient. Routes of administration can beaccomplished through any means known by those skilled in the art. Suchmeans include, but are not limited to, oral, buccal, intravenous,subcutaneous, intramuscular, transdermal, by inhalation and the like.

The term “active agent” as used herein refers to (1) a xanthineoxidoreductase inhibitor or a pharmaceutically acceptable salt thereofor (2) a xanthine oxidase inhibitor or a pharmaceutically acceptablesalt thereof. The term “active agent” and “drug” are usedinterchangeably herein. The solid state form of the active agent used inpreparing the dosage forms of the present disclosure is not critical.For example, active agent used in preparing the modified release dosageforms of the present disclosure can be amorphous or crystalline. Thefinal dosage form contains at least a detectable amount of crystallineactive agent. The crystalline nature of the active agent can be detectedusing powder X-ray diffraction analysis, by differential scanningcalorimetry or any other techniques known in the art.

The term “C_(max)” refers to the maximum observed plasma concentrationof a xanthine oxidoreductase inhibitor or salt thereof produced by theingestion of the dosage forms of the present disclosure. Unlessotherwise noted herein, the reported value for the C_(max) is thecentral value of the C_(max). The “central value” of the C_(max) is themean C_(max)±standard deviation.

The term “dosage form” refers to any solid object, semi-solid, or liquidcomposition designed to contain a specific pre-determined amount (i.e.,dose) of a certain active agent. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical ormucosal delivery or subcutaneous implants, or other implanted drugdelivery systems and the like. In one aspect, the dosage forms of thepresent disclosure are considered to be solid, however, they may containliquid or semi-solid components. In another aspect, the dosage form isan orally administered system for delivering an active agent to thegastrointestinal tract of a subject. The dosage form of the presentdisclosure exhibit modified release of the active agent.

By an “effective amount” or a “therapeutically effective amount” of anactive agent is meant a nontoxic but sufficient amount of the activeagent to provide the desired effect. The amount of active agent that is“effective” will vary from subject to subject, depending on the age andgeneral condition of the individual, the particular active agent oragents, and the like. Thus, it is not always possible to specify anexact “effective amount.” However, an appropriate “effective amount” inany individual case may be determined by one of ordinary skill in theart using routine experimentation. For example, the dailytherapeutically effective or prophylactically effective amount ofxanthine oxidoreductase inhibiting compounds administered to a patientin single or divided doses range from about 0.01 to about 750 milligramper kilogram of body weight per day (mg/kg/day). More specifically, apatient may be administered from about 5.0 mg to about 300 mg oncedaily, from about 20 mg to about 240 mg once daily and from about 40 mgto about 120 mg once daily of xanthine oxidoreductase inhibitingcompounds. Of course, it will be understood by one skilled in the artthat other dosage regimens may be utilized, such as dosing more thanonce per day, utilizing extended, controlled, or modified release dosageforms, and the like in order to achieve the desired result.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable excipient,” or a “pharmaceuticallyacceptable additive,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects.

The term “subject” refers to an animal. In one aspect, the animal is amammal, including a human or non-human. The terms patient and subjectmay be used interchangeably herein.

The terms “treating” and “treatment” refer to reduction in severityand/or frequency of symptoms, elimination of symptoms and/or underlyingcause, prevention of the occurrence of symptoms and/or their underlyingcause, and improvement or remediation of damage. Thus, for example,“treating” a patient involves prevention of a particular disorder oradverse physiological event in a susceptible individual as well astreatment of a clinically symptomatic individual by inhibiting orcausing regression of a disorder or disease.

As used herein, the term “xanthine oxidoreductase” refers to at leastone form of xanthine oxidoreductase enzyme, namely xanthine oxidaseand/or xanthine dehydrogenase.

As used herein, the phrase “xanthine oxidoreductase inhibitor” refers toany compound that (1) is an inhibitor of a xanthine oxidoreductase, suchas, but not limited to, xanthine oxidase; and (2) chemically, does notcontain a purine ring in its structure (i.e. is a “non-purine”analogue). The phrase “xanthine oxidoreductase inhibitor” as definedherein also includes metabolites, polymorphs, solvates and prodrugs ofsuch compounds, including metabolites, polymorphs, solvates and prodrugsof the exemplary compounds described as Formula I and Formula II below.Examples of xanthine oxidoreductase inhibitors include, but are notlimited to,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid and compounds having the following Formula I or Formula II:

wherein R₁ and R₂ are each independently a hydrogen, a hydroxyl group, aCOOH group, an unsubstituted or substituted C₁-C₁₀ alkyl group, anunsubstituted or substituted C₁-C₁₀ alkoxy, an unsubstituted orsubstituted hydroxyalkoxy, a phenylsulfinyl group or a cyano (—CN)group;

wherein R₃ and R₄ are each independently a hydrogen or A, B, C or D asshown below:

wherein T connects or attaches A, B, C or D to the aromatic ring shownabove at R₁, R₂, R₃ or R₄.

wherein R₅ and R₆ are each independently a hydrogen, a hydroxyl group, aCOOH group, an unsubstituted or substituted C₁-C₁₀ alkyl group, anunsubstituted or substituted C₁-C₁₀ alkoxy, an unsubstituted orsubstituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;

wherein R₇ and R₈ are each independently a hydrogen, a hydroxyl group, aCOOH group, an unsubstituted or substituted C₁-C₁₀ alkyl group, anunsubstituted or substituted C₁-C₁₀ alkoxy, an unsubstituted orsubstituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;

wherein R₉ is an unsubstituted pyridyl group or a substituted pyridylgroup; and

wherein R₁₀ is a hydrogen or a lower alkyl group, a lower alkyl groupsubstituted with a pivaloyloxy group and in each case, R₁₀ bonds to oneof the nitrogen atoms in the 1,2,4-triazole ring shown above in FormulaI.

wherein R₁₁ and R₁₂ are each independently a hydrogen, a substituted orunsubstituted lower alkyl group, a substituted or unsubstituted phenyl(the substituted phenyl in this Formula II refers to a phenylsubstituted with a halogen or lower alkyl, and the like. Examplesinclude, but are not limited to, p-tolyl and p-chlorophenyl), or R₁₁ andR₁₂ may together form a four- to eight-membered carbon ring togetherwith the carbon atom to which they are attached;

wherein R₁₃ is a hydrogen or a substituted or unsubstituted lower alkylgroup;

wherein R₁₄ is one or two radicals selected from a group consisting of ahydrogen, a halogen, a nitro group, a substituted or unsubstituted loweralkyl group, a substituted or unsubstituted phenyl (the substitutedphenyl in this Formula II refers to a phenyl substituted with a halogenor lower alkyl group, and the like. Examples include, but are notlimited to, p-tolyl and p-chlorophenyl), —OR₁₆ and —SO₂NR₁₇R_(17′),wherein R₁₆ is a hydrogen, a substituted or unsubstituted lower alkyl, aphenyl-substituted lower alkyl, a carboxymethyl or ester thereof, ahydroxyethyl or ether thereof, or an allyl; R₁₇ and R_(17′) are eachindependently a hydrogen or a substituted or unsubstituted lower alkylgroup;

wherein R₁₅ is a hydrogen or a pharmaceutically active ester-forminggroup;

wherein A is a straight or branched hydrocarbon radical having one tofive carbon atoms;

wherein B is a halogen, an oxygen, or an ethylenedithio;

wherein Y is an oxygen, a sulfur, a nitrogen or a substituted nitrogen;

wherein Z is an oxygen, a nitrogen or a substituted nitrogen; and

the dotted line refers to either a single bond, a double bond, or twosingle bonds (for example, when B is ethylenedithio, the dotted lineshown in the ring structure can be two single bonds).

As used herein, the term “lower alkyl(s)” group refers to a C₁-C₇ alkylgroup, including, but not limited to, including methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, heptal and the like.

As used herein, the term “lower alkoxy” refers to those groups formed bythe bonding of a lower alkyl group to an oxygen atom, including, but notlimited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,pentoxy, hexoxy, heptoxy and the like.

As used herein, the term “lower alkylthio group” refers to those groupsformed by the bonding of a lower alkyl to a sulfur atom.

As used herein, the term “halogen” refers to fluorine, chlorine, bromineand iodine.

As used herein, the term “substituted pyridyl” refers to a pyridyl groupthat can be substituted with a halogen, a cyano group, a lower alkyl, alower alkoxy or a lower alkylthio group.

As used herein, the term “four- to eight-membered carbon ring” refers tocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and thelike.

As used herein, the phrase “pharmaceutically active ester-forming group”refers to a group which binds to a carboxyl group through an ester bond.Such ester-forming groups can be selected from carboxy-protecting groupscommonly used for the preparation of pharmaceutically active substances,especially prodrugs. For the purpose of the present disclosure, saidgroup should be selected from those capable of binding to compoundshaving Formula II wherein R₁₅ is hydrogen through an ester bond.Resultant esters are effective to increase the stability, solubility,and absorption in gastrointestinal tract of the correspondingnon-esterified forms of said compounds having Formula II, and alsoprolong the effective blood-level of it. Additionally, the ester bondcan be cleaved easily at the pH of body fluid or by enzymatic actions invivo to provide a biologically active form of the compound havingFormula II. Preferred pharmaceutically active ester-forming groupsinclude, but are not limited to, 1-(oxygen substituted)-C₂ to C₁₅ alkylgroups, for example, a straight, branched, ringed, or partially ringedalkanoyloxyalkyl groups, such as acetoxymethyl, acetoxyethyl,propionyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl,cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethyl, and thelike, C₃ to C₁₅ alkoxycarbonyloxyalkyl groups, such asethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl,isopropoxycarbonyloxypropyl, t-butoxycarbonyloxyethyl,isopentyloxycarbonyloxypropyl, cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxycarbonyloxyisopropyl, and the like, C₂to C₈ alkoxyalkyls, such as methoxy methyl, methoxy ethyl, and the like,C₄ to C₈ 2-oxacycloalkyls such as, tetrahydropyranyl, tetrahydrofuranyl,and the like, substituted C₈ to C₁₂ aralkyls, for example, phenacyl,phthalidyl, and the like, C₆ to C₁₂ aryl, for example, phenyl xylyl,indanyl, and the like, C₂ to C₁₂ alkenyl, for example, allyl,(2-oxo-1,3-dioxolyl)methyl, and the like, and[4,5-dihydro-4-oxo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl, and thelike.

In R₁₆ in Formula II, the term “ester” as used in the phrase “the esterof carboxymethyl” refers to a lower alkyl ester, such as methyl or ethylester; and the term “ether” used in the phrase “the ether ofhydroxyethyl” means an ether which is formed by substitution of thehydrogen atom of hydroxyl group in the hydroxyethyl group by aliphaticor aromatic alkyl group, such as benzyl.

The carboxy-protecting groups may be substituted in various ways.Examples of substituents include halogen atom, alkyl groups, alkoxygroups, alkylthio groups and carboxy groups.

As used herein, the term “straight or branched hydrocarbon radical” inthe definition of A in Formula II above refers to methylene, ethylene,propylene, methylmethylene, or isopropylene.

As used herein, the substituent of the “substituted nitrogen” in thedefinition of Y and Z in Formula II above are hydrogen, lower alkyl, oracyl.

As used herein, the term “phenyl-substituted lower alkyl” refers to alower alkyl group substituted with phenyl, such as benzyl, phenethyl orphenylpropyl. As used herein, the term “prodrug” refers to a derivativeof the compounds shown in the above-described Formula I and Formula IIthat have chemically or metabolically cleavable groups and become bysolvolysis or under physiological conditions compounds that arepharmaceutically active in vivo. Esters of carboxylic acids are anexample of prodrugs that can be used in the dosage forms of the presentdisclosure. Methyl ester prodrugs may be prepared by reaction of acompound having the above-described formula in a medium such as methanolwith an acid or base esterification catalyst (e.g., NaOH, H₂SO₄). Ethylester prodrugs are prepared in similar fashion using ethanol in place ofmethanol.

Examples of compounds having the above Formula I are:2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid(also known as “febuxostat”),2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±) or3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole.

Preferred compounds having the above Formula I are:2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid. These preferred compounds have also been found not have an effectat a therapeutically effective amount in a subject on the activity ofany of the following enzymes involved in purine and pyrimidinemetabolism: guanine deaminase, hypoxanthine-guaninephosphoribosyltransferse, purine nucleotide phosphorylase, orotatephosphoribosyltransferase or orotidine-5-monophosphate decarboxylase(i.e., meaning that it is “selective” for none of these enzymes whichare involved in purine and pyrimidine metabolism). Assays fordetermining the activity for each of the above-described enzymes isdescribed in Yasuhiro Takano, et al., Life Sciences, 76:1835-1847(2005). These preferred compounds have also been referred to in theliterature as nonpurine, selective inhibitors of xanthine oxidase(NP/SIXO).

Examples of compounds having the above Formula II are described in U.S.Pat. No. 5,268,386 and EP 0 415 566 A1, and are incorporated, in theirentirety, herein.

With the exception of pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±), methods formaking xanthine oxidoreductase inhibiting compounds of Formulas I and IIfor use in the methods of the present disclosure are known in the artand are described, for example, in U.S. Pat. Nos. 5,268,386, 5,614,520,6,225,474, 7,074,816 and EP 0 415 566 A1 and in the publicationsIshibuchi, S. et al., Bioorg. Med. Chem. Lett., 11:879-882 (2001) andwhich are each herein incorporated by reference. Other xanthineoxidoreductase inhibiting compounds can be found using xanthineoxidoreductase and xanthine in assays to determine if such candidatecompounds inhibit conversion of xanthine into uric acid. Such assays arewell known in the art.

Pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±) is available fromOtsuka Pharmaceutical Co. Ltd. (Tokyo, Japan) and is described in thefollowing publications: Uematsu T., et al., “Pharmacokinetic andPharmacodynamic Properties of a Novel Xanthine Oxidase Inhibitor,BOF-4272, in Healthy Volunteers, J. Pharmacology and ExperimentalTherapeutics, 270:453-459 (August 1994), Sato, S., A Novel XanthineDeydrogenase Inhibitor (BOF-4272). In Purine and Pyrimidine Metabolismin Man, Vol. VII, Part A, ed. By P. A. Harkness, pp. 135-138, PlenumPress, New York. Pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±) can be made usingroutine techniques known in the art.

II. Methods of Treatment

The present disclosure relates to methods of treating hyperuricemia inpatients that also require treatment with theophylline, without havingto adjust the theophylline dose to account for the hyperuricemiatreatment. Specifically, the present disclosure provides in one aspect,a method of treating hyperuricemia in a patient in need of treatmentthereof, the method comprising the step of: administering to a patientsuffering from hyperuricemia and at least one secondary disease state, atherapeutically effective amount of at least one xanthine oxidoreductaseinhibitor, wherein said subject is also receiving a concomitantadministration of theophylline to treat the at least one second diseasestate, and further wherein (i) the administration of the at least onexanthine oxidoreductase inhibitor to said patient does not result intheophylline toxicity to said patient; and (ii) administration of thetheophylline is in an amount ranging from about 90% to about 110% of amanufacturer's recommended theophylline dosage amount in the absence ofadministration of at least one xanthine oxidoreductase inhibitor. Morespecifically, administration of the theophylline can be in an amountranging from about 91% to about 109%, about 91% to about 108%, about 91%to about 107%, about 91% to about 106%, about 91% to about 105%, about91% to about 104%, about 91% to about 103%, about 91% to about 102%,about 91% to about 101%, about 92% to about 109%, about 92% to about108%, about 92% to about 107%, about 92% to about 106%, about 92% toabout 105%, about 92% to about 104%, about 92% to about 103%, about 92%to about 102%, about 92% to about 101%, about 93% to about 109%, about93% to about 108%, about 93% to about 107%, about 93% to about 106%,about 93% to about 105%, about 93% to about 104%, about 93% to about103%, about 93% to about 102%, about 93% to about 101%, about 94% toabout 109%, about 94% to about 108%, about 94% to about 107%, about 94%to about 106%, about 94% to about 105%, about 94% to about 104%, about94% to about 103%, about 94% to about 102%, about 94% to about 101%,about 95% to about 109%, about 95% to about 108%, about 95% to about107%, about 95% to about 106%, about 95% to about 105%, about 95% toabout 104%, about 95% to about 103%, about 95% to about 102%, about 95%to about 101%, about 96% to about 109%, about 96% to about 108%, about96% to about 107%, about 96% to about 106%, about 96% to about 105%,about 96% to about 104%, about 96% to about 103%, about 96% to about102%, about 96% to about 101%, about 97% to about 109%, about 97% toabout 108%, about 97% to about 107%, about 97% to about 106%, about 97%to about 105%, about 97% to about 104%, about 97% to about 103%, about97% to about 102%, about 97% to about 101%, about 98% to about 109%,about 98% to about 108%, about 98% to about 107%, about 98% to about106%, about 98% to about 105%, about 98% to about 104%, about 98% toabout 103%, about 98% to about 102%, about 98% to about 101%, about 99%to about 109%, about 99% to about 108%, about 99% to about 107%, about99% to about 106%, about 99% to about 105%, about 99% to about 104%,about 99% to about 103%, about 99% to about 102% or about 99% to about101% of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.

In another aspect, the present disclosure provides a method of treatinghyperuricemia in a patient in need of treatment thereof, the methodcomprising the step of: administering to a patient suffering fromhyperuricemia and at least one secondary disease state, atherapeutically effective amount of at least one xanthine oxidoreductaseinhibitor, wherein said subject will also be receiving a concomitantadministration of theophylline (“will also be receiving” meaning suchas, concurrently with the xanthine oxidoreductase inhibitor, orsubsequent to the initiation of treatment with the xanthineoxidoreductase inhibitor) to treat the at least one second diseasestate, and further wherein (i) the administration of the at least onexanthine oxidoreductase inhibitor to said patient does not result intheophylline toxicity to said patient; and (ii) administration of thetheophylline is in an amount ranging from about 90% to about 110% of amanufacturer's recommended theophylline dosage amount in the absence ofadministration of at least one xanthine oxidoreductase inhibitor. Morespecifically, administration of the theophylline can be in an amountranging from about 91% to about 109%, about 91% to about 108%, about 91%to about 107%, about 91% to about 106%, about 91% to about 105%, about91% to about 104%, about 91% to about 103%, about 91% to about 102%,about 91% to about 101%, about 92% to about 109%, about 92% to about108%, about 92% to about 107%, about 92% to about 106%, about 92% toabout 105%, about 92% to about 104%, about 92% to about 103%, about 92%to about 102%, about 92% to about 101%, about 93% to about 109%, about93% to about 108%, about 93% to about 107%, about 93% to about 106%,about 93% to about 105%, about 93% to about 104%, about 93% to about103%, about 93% to about 102%, about 93% to about 101%, about 94% toabout 109%, about 94% to about 108%, about 94% to about 107%, about 94%to about 106%, about 94% to about 105%, about 94% to about 104%, about94% to about 103%, about 94% to about 102%, about 94% to about 101%,about 95% to about 109%, about 95% to about 108%, about 95% to about107%, about 95% to about 106%, about 95% to about 105%, about 95% toabout 104%, about 95% to about 103%, about 95% to about 102%, about 95%to about 101%, about 96% to about 109%, about 96% to about 108%, about96% to about 107%, about 96% to about 106%, about 96% to about 105%,about 96% to about 104%, about 96% to about 103%, about 96% to about102%, about 96% to about 101%, about 97% to about 109%, about 97% toabout 108%, about 97% to about 107%, about 97% to about 106%, about 97%to about 105%, about 97% to about 104%, about 97% to about 103%, about97% to about 102%, about 97% to about 101%, about 98% to about 109%,about 98% to about 108%, about 98% to about 107%, about 98% to about106%, about 98% to about 105%, about 98% to about 104%, about 98% toabout 103%, about 98% to about 102%, about 98% to about 101%, about 99%to about 109%, about 99% to about 108%, about 99% to about 107%, about99% to about 106%, about 99% to about 105%, about 99% to about 104%,about 99% to about 103%, about 99% to about 102% or about 99% to about101% of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.

The method of the current invention comprises the co-administration of axanthine oxidoreductase inhibitor and theophylline. The term xanthineoxidoreductase includes multiple therapeutic compounds, which have beendescribed previously, and which are incorporated in their entiretyherein. Generally, xanthine oxidoreductase inhibitors are compounds thatinhibit the activity of xanthine oxidase, an enzyme involved in purinemetabolism. In humans, inhibition of xanthine oxidase reduces theproduction of uric acid, which leads to secondary disease states such asgout, and other related diseases. Xanthine oxidoreductase inhibitorstypically are classified as one of two types: purine analogues andnon-purine analogues. The xanthine oxidoreductase inhibitors of thecurrent invention include non-purine analogues, and, as notedpreviously, lack a purine ring in its chemical structure. In oneembodiment, the xanthine oxidoreductase inhibitor includes, but is notlimited to2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid(also known as “febuxostat”),2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±) or3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole. Inanother embodiment, the xanthine oxidoreductase inhibitor includes2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, and pharmaceutically acceptable salts thereof. In a furtherembodiment, the xanthine oxidoreductase inhibitor is2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acidand pharmaceutically acceptable salts thereof.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, meansthose salts of compounds of the invention that are safe and effectivefor administration to a patient and that do not adversely affect thetherapeutic qualities of the compound. Pharmaceutically acceptable saltsinclude salts of acidic or basic groups present in compounds of theinvention. Pharmaceutically acceptable acid addition salts include, butare not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, pantothenate, bitartrate,ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids. Suitable base salts include, but are not limited to,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. For a review on pharmaceutically acceptable saltssee Berge et al., J. Pharm. Sci., 1977; 66:1-19, incorporated herein byreference, in its entirety.

One of skill in the art will also understand that the xanthineoxidoreductase inhibitors incorporated into the methods of the currentinvention may also incorporate pharmaceutically acceptable excipients.The dosage forms of the present disclosure will typically includepharmaceutically acceptable excipients. As is well known to thoseskilled in the art, pharmaceutical excipients are routinely incorporatedinto solid dosage forms to alter the physical and chemicalcharacteristics of the dosage form. This is done to ease themanufacturing process as well as to improve the performance of thedosage form. Common excipients include, but are not limited to diluents,bulking agents, lubricants, binders, preservatives, antioxidants, andcombinations thereof.

As used herein, the term “hyperuricemia” denotes a disease state inwhich the patient has as an elevation in serum urate (sUA) levelsgreater than or equal to 6.0 mg/dL in women and men. Many factorscontribute to hyperuricemia, including: genetics, insulin resistance,hypertension, renal insufficiency, obesity, diet, use of diuretics, andconsumption of alcoholic beverages. Causes of hyperuricemia can beclassified into three functional types: increased production of uricacid, decreased excretion of uric acid, and mixed type, incorporatingboth of the previous etiologies. Increased production etiologies resultfrom high levels of purine in the diet and increased purine metabolism.Decreased excretion etiologies result from kidney disease, certaindrugs, and competition for excretion between uric acid and othermolecules. Mixed causes include high levels of alcohol and/or fructosein the diet, and starvation. Hyperuricemia typically develops into goutwhen urate crystals are formed from supersaturated body fluids anddeposited in joints, tophi, and parenchymal organs due to a disorder inthe urate metabolism. Uric acid is the end product of purine metabolismand is generated in the cascade of hypoxantine→xanthine→uric acid.

In addition to suffering from hyperuricemia and at least one seconddisease state, the patients being treated according to the methods ofthe present disclosure may also be suffering from at least one third (ormore) additional disease states. These third or more additional diseasestates include, but are not limited to, gout, hypertension, chronicstable angina, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty joint disease, tophaceous gout, uric acid urolithiasis,uric acid nephropathy, progressive renal disease, and combinationsthereof. Alternatively, the patients being treated according to themethods of the present invention may be suffering from both gout andhyperuricemia. In such instances, the patient will also be sufferingfrom at least one third disease state. The patient is or will beconcomitantly administered theophylline to treat the at least thirddisease state. The at least one third disease state includes, but is notlimited to asthma, acute bronchitis, chronic bronchitis, emphysema,neonatal apnea, neonatal bradycardia and combinations thereof. Inaddition, the patient may also be suffering from at least one fourth (ormore) additional disease states. These fourth or more additional diseasestates include, but are not limited to, hypertension, chronic stableangina, renal failure, nephrolithiasis, acute gouty arthritis, chronicgouty joint disease, tophaceous gout, uric acid urolithiasis, uric acidnephropathy, progressive renal disease, and combinations thereof.

The methods of the current disclosure are directed to treating patientswith secondary disease states that are indicated for, or requiretheophylline treatment. Theophylline is a methylxanthine compound usedin the treatment of respiratory diseases resulting from airwayconstriction. Theophylline elicits a physiological response by twoprimary mechanisms, including competitive nonselective phosphodiesteraseinhibitor, which raises intracellular cAMP, activates PKA, inhibitsTNF-alpha and inhibits leukotriene synthesis, and reduces inflammationand innate immunity; and nonselective adenosine receptor antagonism,antagonizing A1, A2, and A3 receptors almost equally, which explainsmany of its cardiac effects and some of its anti-asthmatic effects. Oneskilled in the art will appreciate that the theophylline compound, asdescribed herein is also known by its chemical name,1,3-dimethyl-7H-purine-2,6-dione, its CAS Number, 58-55-9, and amultitude of brand name theophylline pharmaceutical products,incorporating theophylline as at least one of the active pharmaceuticalingredients. The theophylline component of the current methods alsoencompasses immediate release formulations, in addition to modifiedrelease formulations, including extended release, controlled release,and delayed release theophylline dosage forms. Dosage forms oftheophylline may include tablets, capsules, sprinkle caps, liquidformulations, such as solutions and suspensions, and parenteral dosageforms including intravenous, intramuscular, intraarterial,intracerebral, intradermal, intrathecal, and intracerebral dosage forms,and subcutaneous dosage forms.

The methods of the current disclosure allow for theophylline to continueto be administered according to the manufacturer's suggested dosing ofthe compound. As used herein, the phrase “manufacturer's suggesteddosing” signifies the dosing disclosed in the package insert of thetheophylline dosage form and available in a variety of pharmaceuticaltreatment references. The methods of the current disclosure encompassthe recommended dosing for all dosage forms, and include the treatmentof all patients, for all disease states in which theophylline treatmentmay be effective. For example, a manufacturer's suggested dosing fororal theophylline may be 4-6 mg/kg. Thus, as described previouslyherein, in the present disclosure, administration of the theophylline isin an amount ranging from about 90% to about 110% of a manufacturer'srecommended theophylline dosage amount in the absence of administrationof at least one xanthine oxidoreductase inhibitor. If the manufacturer'ssuggested dosing is 4-6 mg/kg, about 90% to about 110% would be fromabout 3.6 to about 6.6 mg/kg.

The methods of the current disclosure are directed to treatinghyperuricemia in patients having a secondary disease state that isindicated for, or is being treated with theophylline. The secondarydisease states may include chronic obstructive pulmonary disease (COPD),chronic obstructive lung disease (COLD), chronic obstructive airwaydisease (COAD), chronic airflow limitation (CAL) and chronic obstructiverespiratory disease (CORD), asthma, acute bronchitis, chronicbronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof. It is also contemplated that the patient requiringtreatment for hyperuricemia may suffer from at least one additionaldisease state. Generally, the at least one additional disease state maybe secondary to the patient's hyperuricemia, or may derive from anetiology unrelated to the hyperuricemia. Examples of the at least oneadditional disease state include, but are not limited to, gout,hypertension, renal failure, nephrolithiasis, acute gouty arthritis,chronic gouty arthritis, tophaceous gout, uric acid urolithiasis, uricacid nephropathy, progressive renal disease, and combinations thereof.

The methods of the current disclosure are based on the surprisingfindings that certain xanthine oxidoreductase inhibitors may beadministered concomitantly with theophylline without adversely affectingblood serum levels and theophylline, and, consequently, avoiding thetypical adjustment in dosing due to hyperuricemia treatment.Theophylline is metabolized by cytochrome P-450 (hereinafter “CYP 450”)to 1-methylxanthine, 3-methylxanthine, and 1,3-methyluric acid. Further,metabolism of 1-methylxanthine to 1-methyluric acid is mediated byxanthine oxidase. The xanthine oxidoreductase inhibitors describedherein are not expected to have any inhibitory effect on CYP 450involved in the metabolism of theophylline; however, because thexanthine oxidoreductase inhibitors are non-purine selective inhibitorsof xanthine oxidase, it is generally expected that the compounds affectthe xanthine oxidase mediate metabolism of theophylline and willdecrease the clearance of theophylline, leading to increasedtheophylline serum levels. As stated previously, theophylline has anarrow therapeutic window, and even small increases in blood serumlevels of the compound may result in serious adverse effects for thepatient. However, the inventors surprisingly found that theadministration of the xanthine oxidoreductase inhibitors describedherein do not adversely affect theophylline serum levels, and thatadjustment of theophylline treatment dosages is not required. Additionaldetails pertaining to the pharmacokinetic parameters of thecoadministration of a xanthine oxidoreductase inhibitor and theophyllineare described in the Examples.

Prior to the discovery of the present invention, in previous studiesusing the xanthine oxidoreductase inhibitor febuxostat, subjects takingconcomitant therapy with certain medications, including theophylline,could be enrolled in the study only if the certain excluded medicationwas discontinued for a certain length of time. For example, as shown inTable 1 below, febuxostat study F-GT06-153 specifically provided thatsubjects taking theophylline could not be entrolled in the study, unlessthe theophylline was discontinued at least 30 days prior to the day 1randomization visit.

TABLE 1 Inclusion Criteria for Febuxostat Study F-GT06-153 “5.2.4Prohibited Concomitant Therapy Subjects may not take any medication(other than study drug) for the purpose of lowering sUA levels. Subjectswho have taken any of the excluded medications listed below, prior tothe study, can be enrolled into the study if the excluded medication isdiscontinued at least 30 days prior to Day 1/Randomization Visit. Thefollowing medications are not to be administered 30 days prior or duringthe study: Any other urate-lowering drug, other than study drug; Use ofNSAIDs and COX-2 inhibitors other than protocol required prophylaxistherapy (short-term use of NSAIDs and COX-2 inhibitors for treatment ofgout flares is allowed); Salicylates (chronic use of aspirin ≦ 325mg/day is allowed); Thiazide diuretics; Losartan; Azathioprine;Mercaptopurine; Theophylline; IV Colchicine; Cyclosporine;Cyclophosphamide; Pyrazinamide; Sulfamethoxazole/trimethoprim; Use ofcorticosteroids (chronic prednisone ≦ 10 mg/ day or its equivalent andshort-term use of higher doses of prednisone for treatment of goutflares is allowed); Changes in hormone replacement therapy or oralcontraceptive therapy within 3 months of the Day 1/Randomization Visitor during the course of the study.”

As is evident from Table 1 above, the coadministration of theophyllineand urate-lowering therapies is a significant clinical concern, and onethat must be considered prior to initiation of urate-lowering therapies.

While hyperuricemia is one of the primary disease states treated by thexanthine oxidoreductase inhibitors discussed herein, one of skill in theart will appreciate that the methods of the current disclosure areequally applicable to other disease states that are typically treated byadministration of one or more xanthine oxidoreductase inhibitors. Theseother disease states include, but are not limited to, gout, prostatitis,inflammatory bowel disease, QT interval prolongation, myocardialinfarction, cardiac hypertrophy, hypertension, nephrolithiasis, renalimpairment, chronic kidney disease, metabolic syndrome (also referred toas “Syndrome X” and includes, at least one of abdominal obesity,atherogenic dyslipidemia, insulin resistance, glucose intolerance, aprothrombotic state or a proinflammatory state), diabetes, diabeticnephropathy, congestive heart failure and combinations thereof (theseconditions are sometimes collectively referred to herein as “at leastone first disease state”). Accordingly, the current methods encompasstreating a patient having one of the aforementioned at least one firstdisease state and also having a second disease state requiringtheophylline treatment, through the administration of a xanthineoxidoreductase inhibitor without significant adjustment of themanufacturer's suggested dosing, and without inducing theophyllinetoxicity. Moreover, the current methods further encompass treating apatient having one of the aforementioned at least one first diseasestate, at least one second disease state requiring the theophyllinetreatment and at least one third disease state. In addition to sufferingfrom hyperuricemia and at least one second disease state, the patientsbeing treated according to the methods of the present disclosure mayalso be suffering from at least one third (or more) additional diseasestates. These third or more additional disease states include, but arenot limited to, gout, hypertension, chronic stable angina, renalfailure, nephrolithiasis, acute gouty arthritis, chronic gouty jointdisease, tophaceous gout, uric acid urolithiasis, uric acid nephropathy,progressive renal disease, and combinations thereof.

By way of example, and not of limitation, examples of the presentdisclosure will now be given.

Example 1 Effects of Multiple Febuxostat Doses on the Pharmacokineticsof Theophylline Administration

An experiment was performed to determine the effects of multiple dosesof a xanthine oxidoreductase inhibitor,2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid, also known as “febuxostat”, on theophylline doses. The experimentwas a phase I, double-blind, randomized, 2-period crossover study, inwhich 24 patients (12 male and 12 female) were enrolled in the study.Specifically, the total duration of the study was approximately 8 weeks(60 days), consisting of a Screening Period (Days−28 to −2), Check-in(Day −1) for Period 1, 7-day Treatment, a Washout Period (minimum of 7days), Check-in for Period 2, 7-day Treatment, Study Exit or EarlyTermination, and a Follow-up phone call 10±2 days after the last dose ofstudy medication. Subjects received both Regimens A and B in randomlyassigned order. These regimens consisted of 7 daily doses ofdouble-blind febuxostat 80 mg (A: two encapsulated febuxostat 40 mgtablets or B: matching placebo) and one dose (on Day 5 of each period)open-label theophylline 400 mg tablet.

On Days 1 to 7 of each period, subjects received febuxostat 80 mg ormatching placebo at approximately 0900 hours after a minimum 10-hourfast, and followed 1 hour later by a standardized breakfast. On Day 5 ofeach period, subjects received a single oral dose of Uniphyl®(theophylline, anhydrous) 400 mg tablet along with the daily dose offebuxostat or matching placebo; food was first allowed 4 hours postdose.Water was available as desired, except for 1 hour before through 1 hourafter study drug administration. Only 240 mL of water was allowed duringdosing. Subjects were discharged in the morning of Day 8 of each Period(1 and 2), after plasma and urine pharmacokinetic sample collections andall study procedures were completed. For Day −1 of Period 2, subjectsreturned to the clinic after a minimum of 7 day washout period. For allsubjects that completed both Periods 1 and 2 (or discontinued the studyprematurely at an Early Termination visit, i.e., withdrew from study), afollow-up phone call was made 10±2 days after the last dose of studymedication or Early Termination (ET). The effect of multiple oral dosesof febuxostat on the pharmacokinetics of a single oral dose oftheophylline were evaluated through measurement of plasma and urineconcentration levels of theophylline at designated time points. Safety,tolerability, and theophylline toxicity were assessed throughout thestudy by monitoring adverse effects, clinical laboratory tests, vitalsigns, ECGs, and physical examination findings.

Theophylline plasma concentrations were determined from 7 mL bloodsamples obtained according to the schedules in Table 1 below. Troughfebuxostat plasma concentrations were determined from 6 mL blood samplesobtained according to the schedules in Table 2.

TABLE 2 Period 1 and 2: Blood Collection Schedules for Determination ofPlasma Concentrations of Theophylline and Febuxostat Blood SampleCollection for Pharmacokinetics Theophylline Febuxostat Day 5 of Periods1 and 2 Predose (up to 30 minutes prior to dosing Predose (up to 30minutes prior to dosing [0 hour]) and at 1, 2, 3, 4, 6, 8, 10, 12, [0hour]) and 14 hours postdose Day 6 of Periods 1 and 2 16, 24, and 32hours post Day 5 dosing Predose (up to 30 minutes prior to dosing [0hour]) Day 7 of Periods 1 and 2 40, 48, and 56 hours post Day 5 dosingNone Day 8 of Periods 1 and 2 64 and 72 hours post Day 5 dosing None

Additionally, to ensure that the drug plasma levels were not altered buysecondary conditions and medications, this experiment required subjectsto abstain from the use of certain medications and other agents prior toand during the testing periods. The excluded medications and agents aresummarized in Table 3 (prescription and nonprescription), includingspecifications on applicable time points through completion of all studyactivities.

TABLE 3 Excluded Medications and Agents 6 weeks prior to 28 days priorto 14 days prior to 48 hours prior to Check-in (Day −1) Check-in (Day−1) Check-in (Day −1) Check-in (Day −1) Nicotine-containing PrescriptionFoods or beverages Alcohol-containing products medications containinggrapefruit or products Seville oranges Hormonal contraceptionOver-the-counter Food or beverages (oral, patch, implant, medications,vitamins, containing caffeine or vaginal ring, or herbal, or dietaryxanthine related injectable) supplements substances Hormone replacementHepatic or renal Charbroiled foods therapy clearance altering agents(erythromycin, cimetidine, barbiturates, phenothiazines, etc) Febuxostator Allopurinol Note: excluded medications are from timepoints throughcompletion of all study activities.Subjects were instructed not to take any medications or nonprescriptiondrugs, vitamins, herbal supplements, or dietary supplements within 28days prior to Check-in (Day −1).

The subjects of the current experiment were administered the appropriatedosage regimens and the pharmacokinetic data were evaluated. Mean plasmatheophylline concentration vs. time profiles (linear and log-linearformats) for the two treatment regimens are depicted in FIG. 1.Additionally, individual and summary statistics of noncompartmentalpharmacokinetic parameter estimates for theophylline followingcoadministration with febuxostat or placebo are presented in Table 4below.

TABLE 4 Summary of Theophylline Pharmacokinetic Parameter EstimatesFollowing an Oral Dose of 400 mg Theophylline Coadministered With 80 mgFebuxostat or Matching Placebo Tmax Cmax AUC(0-tlqc) AUC(0-inf)(a) T½(a)CL/F(a) Vz/F(a) (hr) (μg/mL) (μg · hr/mL) (μg · hr/mL) (hr) (mL/h) (mL)Theophylline + Febuxostat (Regimen A) N 23 23 23 18 18 18 18 Mean8.43(b) 4.39 122 114 9.69(c) 4430 56900 SD 4.62 1.74 55.7 53.4 2.32 237020400 CV % 55 40 45 47 24 53 36 Theophylline + Placebo (Regimen B) N 2323 23 18 18 18 18 Mean 7.05(b) 4.14 115 107 9.69(c) 4430 58200 SD 2.881.19 50.3 49.9 2.07 1930 17200 CV % 41 29 44 46 21 44 30 Regimen A:Febuxostat 80 mg (two 40 mg encapsulated tablets) QD for 7 consecutivedays and a single oral dose of theophylline, anhydrous 400 mg tablet onDay 5. Regimen B: Matching placebo for febuxostat 80 mg (two 40 mgencapsulated tablets) QD for 7 consecutive days and a single oral doseof theophylline, anhydrous 400 mg tablet on Day 5. (a)The terminal phaseof the pharmacokinetic profile of theophylline could not be adequatelycharacterized in the remaining subjects. (b)Median Tmax values forRegimens A and B were 6.02 and 6.00 hr, respectively. (c)Harmonic meanT½ values for Regimens A and B were 9.13 and 9.28 hr, respectively.

As illustrated in Table 4 above, theophylline was absorbed with a meanT_(max) value of 7 to 9 hours (median=6 hours) and eliminated with amean terminal half-life of 9.69 hours following oral administration of400 mg theophylline with placebo or febuxostat. Mean theophyllineC_(max) values were 4.14 and 4.39 μg/mL for subjects coadministered withplacebo and febuxostat, respectively. Mean theophylline AUC(0-tlqc)values were 115 μg·hr/mL and 122 μg·hr/mL for subjects coadministeredwith placebo and febuxostat, respectively. Likewise, mean AUC(0-inf)values were also comparable between regimens. The intersubjectvariability (% CV) of C_(max) and AUC(0-tlqc) values of theophyllineranged from 29% to 40% and 44% to 45%, respectively. The estimated meanT_(1/2), CL/F, and V_(z)/F values for theophylline were generallysimilar between the 2 treatment regimens.

TABLE 5 Summary of Total Amount of Theophylline and Its MetabolitesExcreted in Urine Over 72 Hours Following an Oral Dose of 400 mgTheophylline Coadministered With 80 mg Febuxostat or Matching PlaceboTheophylline 1,3-Dimethyluric 1-Methyluric 1-Methylxanthine3-Methylxanthine (mg) acid (mg) acid (mg) (mg) (mg) Theophylline +Febuxostat (Regimen A) N 23 23 23 23 23 Mean 35.0 105.2 3.1 40.1 26.9 SD18.1 23.3 4.0 7.6 9.5 CV % 52 22 127 19 35 Theophylline + Placebo(Regimen B) N 23 23 23 23 23 Mean 35.0 114.8 56.2 0.1 30.9 SD 16.8 32.217.4 0.4 11.6 CV % 48 28 31 337 38 Regimen A: Febuxostat 80 mg (two 40mg encapsulated tablets) QD for 7 consecutive days and a single oraldose of theophylline, anhydrous 400 mg tablet on Day 5. Regimen B:Matching placebo for febuxostat 80 mg (two 40 mg encapsulated tablets)QD for 7 consecutive days and a single oral dose of theophylline,anhydrous 400 mg tablet on Day 5.

As illustrated in Table 5 above, the mean amount of parent drug (i.e.,theophylline) excreted in the urine over a 72 hour interval werecomparable between regimen arms and consistent with the literature. SeeMelethil S et al., Res Commun Chem Pathol Pharmacol., 1982; 35(2):341-4.The mean amounts of 1,3-dimethyluric acid and 3-methylxanthine were alsosimilar between the 2 regimens. In contrast, 1-methyluric acid decreasedand 1-methylxanthine increased in subjects administered theophyllinewith febuxostat compared with those subjects administered theophyllinewith placebo.

A statistical analysis of the data was also performed. The effects ofsequence, period, and regimen on theophylline T_(max), ln(C_(max)),ln(AUC[0-tlqc]), and ln(AUC[0-inf]) following coadministration offebuxostat or placebo were assessed. None of the aforementioned effectswere statistically significant on the pharmacokinetic parameters(P>0.05) observed in the experiment. Further, the bioavailability oftheophylline coadministered with febuxostat (Regimen A) relative to thatof theophylline with placebo (Regimen B) was assessed via pointestimates and 90% confidence intervals for the ratios of the centralvalues for C_(max), AUC(0-tlqc), and AUC(0-inf), and is summarized inTable 6.

TABLE 6 Relative Bioavailability of Febuxostat Following Administrationof a Single Oral Dose of 80 mg Febuxostat 90% Confidence Parameter PointEstimate Interval Regimen A vs Regimen B Cmax 1.03 (0.917, 1.149)AUC(0-tlqc) 1.04 (0.927, 1.156) AUC(0-inf) 1.05 (0.924, 1.189) RegimenA: Febuxostat 80 mg (two 40 mg encapsulated tablets) QD for 7consecutive days and a single oral dose of theophylline, anhydrous 400mg tablet on Day 5. Regimen B: Matching Placebo for febuxostat 80 mg(two 40 mg encapsulated tablets) QD for 7 consecutive days and a singleoral dose of theophylline, anhydrous 400 mg tablet on Day 5. Note: Thepoint estimates and confidence intervals were obtained from theexponentiated results of analysis of the natural logarithm transformeddata.From the statistical analyses of the pharmacokinetic data, the pointestimates for theophylline C_(max), AUC(0-tlqc), and AUC(0-inf) wereclose to 100%, and the 90% confidence intervals for the ratios werewithin the bioequivalence limit of 0.80 to 1.25.

The results of this experiment showed that the maximum observedtheophylline concentration (Cmax) and exposure to theophylline (AUC)were comparable between treatment with febuxostat and treatment withplacebo. Therefore, no adjustment of the theophylline dose was neededwhen coadministered with febuxostat.

What is claimed is:
 1. A method of treating hyperuricemia in a patientin need of treatment thereof, the method comprising the steps of:administering to a patient suffering from hyperuricemia and at least onesecond disease state, a therapeutically effective amount of at least onexanthine oxidoreductase inhibitor, wherein the subject is also receivingconcomitant administration of theophylline to treat the at least onesecond disease state, and further wherein (i) the administration of theat least one xanthine oxidoreductase inhibitor to the patient does notresult in theophylline toxicity to the patient; and (ii) administrationof the theophylline is in an amount ranging from about 90% to about 110%of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.
 2. The method of claim 1, wherein the second disease statecomprises chronic obstructive pulmonary disease, asthma, chronicbronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof.
 3. The method of claim 1, wherein the patient isfurther suffering from at least one third disease state, wherein thethird disease comprises gout, hypertension, chronic stable angina, renalfailure, nephrolithiasis, acute gouty arthritis, chronic gouty jointdisease, tophaceous gout, uric acid urolithiasis, uric acid nephropathy,progressive renal disease, and combinations thereof.
 4. The method ofclaim 1, wherein the theophylline dosage amount ranges from about 95% toabout 105% of a manufacturer's recommended theophylline dosage amount inthe absence of administration of at least one xanthine oxidoreductaseinhibitor.
 5. The method of claim 1, wherein the xanthine oxidoreductaseinhibitor is selected from the group consisting of:2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole, andpharmaceutically acceptable salts thereof.
 6. A method of treatinghyperuricemia in a patient in need of treatment thereof, the methodcomprising the steps of: administering to a patient suffering fromhyperuricemia and at least one second disease state, a therapeuticallyeffective amount at least one xanthine oxidoreductase inhibitor, whereinsaid subject will also be receiving a concomitant administration oftheophylline to treat the at least one second disease state, and furtherwherein (i) the administration of the at least one xanthineoxidoreductase inhibitor to said patient will not result in theophyllinetoxicity to said patient; and (ii) administration of the theophyllinewill be in an amount ranging from about 90% to about 110% of amanufacturer's recommended theophylline dosage amount in the absence ofadministration of at least one xanthine oxidoreductase inhibitor.
 7. Themethod of claim 6, wherein the second disease state comprises chronicobstructive pulmonary disease, asthma, chronic bronchitis, emphysema,neonatal apnea, neonatal bradycardia, and combinations thereof.
 8. Themethod of claim 6, wherein the theophylline dosage amount ranges fromabout 95% to about 105% of a manufacturer's recommended theophyllinedosage amount in the absence of administration of at least one xanthineoxidoreductase inhibitor.
 9. The method of claim 6, wherein the seconddisease state comprises chronic obstructive pulmonary disease, asthma,chronic bronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof.
 10. The method of claim 6, wherein the patient isfurther suffering from at least one third disease state, wherein thethird disease comprises gout, hypertension, chronic stable angina, renalfailure, nephrolithiasis, acute gouty arthritis, chronic gouty jointdisease, tophaceous gout, uric acid urolithiasis, uric acid nephropathy,progressive renal disease, and combinations thereof.
 11. The method ofclaim 6, wherein the theophylline dosage amount ranges from about 95% toabout 105% of a manufacturer's recommended theophylline dosage amount inthe absence of administration of at least one xanthine oxidoreductaseinhibitor.
 12. The method of claim 6, wherein the xanthineoxidoreductase inhibitor is selected from the group consisting of:2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole, andpharmaceutically acceptable salts thereof.
 13. The method of claim 6,wherein the patient suffering from hyperuricemia and the at least onesecond disease state initiates treatment with theophylline concurrentlywith the xanthine oxidoreductase inhibitor, or subsequent to theinitiation of treatment with the xanthine oxidoreductase inhibitor. 14.The method of claim 6, wherein the patient suffering from hyperuricemiaand the at least one second disease state is previously administeredtheophylline prior to initiation of treatment with the xanthineoxidoreductase inhibitor.
 15. A method of treating a patient sufferingfrom at least one first disease state and in need of treatment thereof,the method comprising the step of: administering to a patient sufferingfrom at least one first disease state and at least one second diseasestate, a therapeutically effective amount of at least one xanthineoxidoreductase inhibitor, wherein the subject is also receivingconcomitant administration of theophylline to treat the at least onesecond disease state, and further wherein (i) the administration of theat least one xanthine oxidoreductase inhibitor to the patient does notresult in theophylline toxicity to the patient; and (ii) administrationof the theophylline is in an amount ranging from about 90% to about 110%of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.
 16. The method of claim 15, wherein the first disease stateis gout, prostatitis, inflammatory bowel disease, QT intervalprolongation, myocardial infarction, cardiac hypertrophy, hypertension,nephrolithiasis, renal impairment, chronic kidney disease, metabolicsyndrome, diabetes, diabetic nephropathy, congestive heart failure orcombinations thereof.
 17. The method of claim 15, wherein the seconddisease state comprises chronic obstructive pulmonary disease, asthma,chronic bronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof.
 18. The method of claim 15, wherein the patient isfurther suffering from at least one third disease state, wherein thethird disease comprises gout, hypertension, chronic stable angina, renalfailure, nephrolithiasis, acute gouty arthritis, chronic gouty jointdisease, tophaceous gout, uric acid urolithiasis, uric acid nephropathy,progressive renal disease, and combinations thereof.
 19. The method ofclaim 15, wherein the theophylline dosage amount ranges from about 95%to about 105% of a manufacturer's recommended theophylline dosage amountin the absence of administration of at least one xanthine oxidoreductaseinhibitor.
 20. The method of claim 15, wherein the xanthineoxidoreductase inhibitor is selected from the group consisting of:2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole, andpharmaceutically acceptable salts thereof.
 21. A method of treatinghyperuricemia in a patient suffering from gout and in need of treatmentthereof, the method comprising the step of: administering to a patientsuffering from gout and hyperuricemia and at least one third diseasestate, a therapeutically effective amount of at least one xanthineoxidoreductase inhibitor, wherein the subject is also receivingconcomitant administration of theophylline to treat the at least onethird disease state, and further wherein (i) the administration of theat least one xanthine oxidoreductase inhibitor to the patient does notresult in theophylline toxicity to the patient; and (ii) administrationof the theophylline is in an amount ranging from about 90% to about 110%of a manufacturer's recommended theophylline dosage amount in theabsence of administration of at least one xanthine oxidoreductaseinhibitor.
 22. The method of claim 21, wherein the third disease statecomprises chronic obstructive pulmonary disease, asthma, chronicbronchitis, emphysema, neonatal apnea, neonatal bradycardia, andcombinations thereof.
 23. The method of claim 21, wherein the patient isfurther suffering from at least one fourth disease state, wherein thefourth disease state is hypertension, chronic stable angina, renalfailure, nephrolithiasis, acute gouty arthritis, chronic gouty jointdisease, tophaceous gout, uric acid urolithiasis, uric acid nephropathy,progressive renal disease, and combinations thereof.
 24. The method ofclaim 21, wherein the theophylline dosage amount ranges from about 95%to about 105% of a manufacturer's recommended theophylline dosage amountin the absence of administration of at least one xanthine oxidoreductaseinhibitor.
 25. The method of claim 21, wherein the xanthineoxidoreductase inhibitor is selected from the group consisting of:2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylicacid,2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid,2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylicacid, 2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid,2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylicacid, 1-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-1H-pyrazole-4-carboxylicacid, 1-3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylicacid, pyrazolo[1,5-a]-1,3,5-triazin-4-(1H)-one,8-[3-methoxy-4-(phenylsulfinyl)phenyl]-sodium salt (±),3-(2-methyl-4-pyridyl)-5-cyano-4-isobutoxyphenyl)-1,2,4-triazole, andpharmaceutically acceptable salts thereof.
 26. The method of claim 21,wherein the patient suffering from gout and hyperuricemia and the atleast one third disease state initiates treatment with theophyllineconcurrently with the xanthine oxidoreductase inhibitor, or subsequentto the initiation of treatment with the xanthine oxidoreductaseinhibitor.
 27. The method of claim 21, wherein the patient sufferingfrom gout and hyperuricemia and the at least one third disease state ispreviously administered theophylline prior to initiation of treatmentwith the xanthine oxidoreductase inhibitor.